Intracellular sensing and body fluid sensing are in demand for a variety of applications from patient monitoring to cell sorting and basic cell function studies. Bio-medical sensors are being developed that can continuously track a wide variety of physiological metrics and activities. Examples include tracking heart rhythm, blood pressure, respiratory rate, the oxygen saturation of hemoglobin, blood glucose concentrations, brain-computer interfacing, and brain waves. Many of these sensors are being integrated with electronics to provide wireless communication. Existing approaches to the sensing needs include voltage-sensitive optical dyes (1, 2) and single-terminal glass (3-5) or carbon (6-8) microelectrodes.
However, these bio-medical sensors have all met with limited acceptance owing to various technical issues. In particular, voltage-sensitive dyes have limitations including pharmacological side effects and phototoxicity (7, 8). While microelectrode probes allow mechanical insertion into tissue and cells, the requirement of either or both direct ionic and electrical contacting between probe tips and cell materials imposes difficult size constraints on this type of probe due to current-drawing (impedance) problems. Both voltage sensitive dyes and microelectrode probes are not amenable to in situ signal amplification, or to formation of an addressable-array
Spatially localized, three-dimensional (3-D), electrically addressable, probe field effect transistor (FET) bio-medical sensing devices would avoid these difficulties. FETs can detect by monitoring the gate (G) electrode current, but they also have the basic advantage that they can sense by detecting gate charge variations without the need for particle current exchange with media such as cellular medium or body fluids; thus, interfacial impedance effects can be minimized. In addition, because signals can be detected by charge changes at gate surfaces, FETs can detect cellular potential (2-5), as well as biological molecules (1). FETs can measure ion flux or electrical signals in cells including neurons. The FET gate electrodes can also be functionalized (e.g., coated by the purposeful chemical bonding of various molecules such as antibodies, antigens, or ligands) to probe for the presence of very specific bio-chemicals within a cell. Unfortunately, FETs require, in addition to a gate electrode, two current flowing electrical contacts, the source (S) and the drain (D). Because of this, almost all biomedical sensing field-effect transistor (FET) probe devices that have been explored have not been 3-D. FET probes have been created with the sensing gate regions, as well as the sources and drains, all on the same planar substrate (9, 10), making design of 3D FET probes and their minimally invasive insertion into a cell or tissue a substantial challenge to-date. An exception to this planar arrangement limitation is a 3-D FET sensing probe device demonstrated by Tian et al. (9); however, that device still had several limitations that included: (a) incorporating the whole FET including gate electrode, source and drain portions in the probe rather than simply the sensing gate region; (b) did not use gate functionalization for specificity; (c) is composed of a source-gate-drain silicon (a brittle material) probe inserted into the cell medium; (d) did not utilize a well-defined gate dielectric; (e) is fundamentally limited to sizes dictated by its Si probe interconnects; and (f) is not amenable to roll-to-roll manufacturing.
Human cells vary from nerve cells with characteristic sizes of about 10 microns to heart cells with characteristic sizes of about 50 microns. In studies of basic probe dimension requirements, it has been found that tip sizes of ˜200 nm to 5 μm are a compromise between being small enough to rupture cell membranes and penetrate into a cell with minimum damage (must be <5 μm) and large enough to yield a contact impedance in current drawing applications that is sufficiently low (must be >200 nm) (1, 2, 11-14).
Thus, there exists a need for a three dimensional biomedical probe sensing structure that has one or more of the attributes of (a) including a self-contained reference-electrode capability if desired, (2) electronic addressability, and being (3) amenable to use with wireless communication circuitry.